Cannabidiol targets a modulatory system for excitatory-inhibitory synaptic coordination, contributing to its anti-seizure action

Rosenberg, E.; Chamberland, S.; Bazelot, M.; Nebet, E.; Wang, X.; McKenzie, S.; Jain, S.; Greenhill, S.; Wilson, M.; Salah, A.; Bailey, S.; Patra, P. H.; Chenouard, N.; Sun, S.; Jones, D.; Buzsaki, G.; Devinsky, O.; Woodhall, G.; Scharfman, H.; Whalley, B.; Tsien, R.

doi:10.1101/2022.09.27.509638

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bioRxiv · 10.1101/2022.09.27.509638

Cannabidiol targets a modulatory system for excitatory-inhibitory synaptic coordination, contributing to its anti-seizure action

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Abstract

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsy, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3[->]CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAAR{gamma}2 and gephyrin puncta. Effects of LPI at both excitatory and inhibitory synapses were eliminated by CBD pretreatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated levels of GPR55 and LPI, and chronic lithium pilocarpine-induced epileptogenesis potentiated the pro-excitatory effects of LPI. We propose that CBD exerts potential therapeutic effect both by blocking synaptic effects of LPI and dampening hyperexcitability.

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Rosenberg, E., Chamberland, S., Bazelot, M., Nebet, E., Wang, X., McKenzie, S., Jain, S., Greenhill, S., Wilson, M., Salah, A., Bailey, S., Patra, P. H., Chenouard, N., Sun, S., Jones, D., Buzsaki, G., Devinsky, O., Woodhall, G., Scharfman, H., Whalley, B., Tsien, R.. 2022-09-28. Cannabidiol targets a modulatory system for excitatory-inhibitory synaptic coordination, contributing to its anti-seizure action. https://doi.org/10.1101/2022.09.27.509638

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